Submissions for variant NM_002528.7(NTHL1):c.244C>T (p.Gln82Ter)

gnomAD frequency: 0.00138  dbSNP: rs150766139

Total submissions: 32

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000657657	SCV000779405	pathogenic	not provided	2020-01-29	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 27712984, 29105096, 31645984, 18515411, 23852950, 26553438, 25525159, 26427841, 25938944, 26559593, 27713038, 27329137, 28306719, 26431160, 27720914, 29454559, 29909963, 30552997, 29900613, 30753826, 31227763, 31243857, 31285513, 30859360, 30248171, 30267214, 30877237, 31263571, 31980526, 32581362, 33193653, 32860789, 32949222)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000657657	SCV000957470	pathogenic	not provided	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln90*) in the NTHL1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NTHL1 are known to be pathogenic (PMID: 25938944, 26559593). This variant is present in population databases (rs150766139, gnomAD 0.4%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with multiple adenomatous polyps and colorectal cancer (PMID: 25938944, 26559593, 27720914). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 192319). For these reasons, this variant has been classified as Pathogenic.
Academic Department of Medical Genetics, University of Cambridge	RCV000850062	SCV000992218	pathogenic	Hereditary cancer-predisposing syndrome	2018-01-26	criteria provided, single submitter	research	Application of AMCG guidelines 2015. Used other ClinVar submission evidence where relevant. Loss of heterozygosity in tumours or immunohistochemistry abnormalities considered functional evidence of pathogenicity.
Ambry Genetics	RCV000850062	SCV001177246	pathogenic	Hereditary cancer-predisposing syndrome	2021-10-18	criteria provided, single submitter	clinical testing	The p.Q90* pathogenic mutation (also known as c.268C>T), located in coding exon 2 of the NTHL1 gene, results from a C to T substitution at nucleotide position 268. This changes the amino acid from a glutamine to a stop codon within coding exon 2. This mutation has been reported in the homozygous or compound heterozygous state in multiple unrelated individuals with polyposis and/or colorectal cancer (Dallosso AR et al. Gut 2008 Sep;57:1252-5; Weren RD et al. Nat. Genet. 2015 Jun;47:668-71; Kuiper RP et al. Oncotarget 2015 Oct;6:34069-70; Timofeeva MN et al. Sci Rep. 2015 Nov 10;5:16286; Rivera et al. N. Engl. J. Med. 2015 Dec;373:e33; Broderick P et al. Gastroenterology 2017 Jan;152:75-77.e4; Belhadj S et al. Clin. Gastroenterol. Hepatol. 2017 Mar;15:461-462; Whitworth J et al. Am J Hum Genet. 2018 Jul 5;103(1):3-18; Fostira F et al. Clin Genet. 2018 Sep 24). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Baylor Genetics	RCV000172911	SCV001482746	pathogenic	Familial adenomatous polyposis 3	2024-03-29	criteria provided, single submitter	clinical testing
Department of Molecular Diagnostics, Institute of Oncology Ljubljana	RCV000172911	SCV001499696	pathogenic	Familial adenomatous polyposis 3	2020-04-02	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000172911	SCV002020560	pathogenic	Familial adenomatous polyposis 3	2023-06-12	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000657657	SCV002047143	pathogenic	not provided	2021-05-18	criteria provided, single submitter	clinical testing	This variant causes the premature termination of NTHL1 protein synthesis. In the published literature, this variant has been reported in numerous compound heterozygous and homozygous individuals affected with colorectal cancer, colorectal adenomas, and other neoplasms in the published literature (PMID: 33193653 (2020), 30753826 (2019), 27720914 (2017), 27713038 (2017), 26559593 (2015), 26553438 (2015), 25938944 (2015), 18515411 (2008)). Based on the available information, this variant is classified as pathogenic.
Mendelics	RCV000172911	SCV002517824	pathogenic	Familial adenomatous polyposis 3	2022-05-04	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000850062	SCV002528946	pathogenic	Hereditary cancer-predisposing syndrome	2022-02-18	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000657657	SCV002551610	pathogenic	not provided	2024-07-31	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000172911	SCV002578948	pathogenic	Familial adenomatous polyposis 3	2022-06-22	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000172911	SCV002584750	pathogenic	Familial adenomatous polyposis 3	2022-07-18	criteria provided, single submitter	clinical testing	The NTHL1 c.268C>T (p.Gln90Ter) change is a nonsense variant that is predicted to cause premature protein truncation and loss of normal protein function. This variant has been reported as homozygous in individuals across multiple families with colon cancer and/or adenomatous polyposis (PMID: 25938944, 27720914, 30248171, 31645984). It has also been reported as compound heterozygous in an individual with adenocarcinoma of the colon and >30 colorectal adenomas (PMID: 26559593). This variant has a maximum subpopulation frequency of 0.35% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). It is referred to as p.Gln82Ter in the NM_002528 transcript. In summary, this variant meets criteria to be classified as pathogenic.
Genetics and Molecular Pathology, SA Pathology	RCV000172911	SCV002761396	pathogenic	Familial adenomatous polyposis 3	2023-03-03	criteria provided, single submitter	clinical testing	The NTHL1 c.244C>T variant is classified as Pathogenic (PVS1, PS4_Moderate, PM3_Strong) The NTHL1 c.244C>T variant is a single nucleotide change which is predicted to result in the premature termination of the protein product at codon 82 (PVS1). The variant has been widely reported in the literature in affected patients (PMID:18515411, 25938944, 26431160, 26559593, 27720914, 31285513) (PS4_Moderate). It has been detected as homozygous in 4 unrelated patients and as compound het with another path/likely path variant in 3 patients (eg. PMID:33454955) (PM3_strong). The variant has been reported in dbSNP (rs150766139), in population databases (gnomAD 204/152138 alleles, 0 hom) and as disease causing in the HGMD database (CM088021). It has been reported as Conflicting interpretations of pathogenicity by other diagnostic laboratories (ClinVar Variation ID: 192319). Unaffected heterozygous carriers of this variant have been reported (PMID:18515411, PMID:25938944, PMID:31285513). Note: this variant is also known as (NM_002528.6):c.268C>T; p.Gln90*.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000172911	SCV003807975	pathogenic	Familial adenomatous polyposis 3	2022-09-02	criteria provided, single submitter	clinical testing	ACMG classification criteria: PVS1 very strong, PM3 strong
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000657657	SCV004026122	pathogenic	not provided	2021-06-08	criteria provided, single submitter	clinical testing	PP5, PP1, BS1
CeGaT Center for Human Genetics Tuebingen	RCV000657657	SCV004033426	pathogenic	not provided	2024-05-01	criteria provided, single submitter	clinical testing	NTHL1: PVS1, PP1:Strong
Human Genetics Bochum, Ruhr University Bochum	RCV000172911	SCV004042766	pathogenic	Familial adenomatous polyposis 3	2023-10-02	criteria provided, single submitter	clinical testing	ACMG criteria used to clasify this variant: PVS1, PS4, PM3_SUP
Myriad Genetics, Inc.	RCV000172911	SCV004188348	pathogenic	Familial adenomatous polyposis 3	2023-09-01	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
Mayo Clinic Laboratories, Mayo Clinic	RCV000657657	SCV004226765	pathogenic	not provided	2023-05-31	criteria provided, single submitter	clinical testing	PP1, PP4, PM3, PS4_moderate, PVS1
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000172911	SCV004808141	pathogenic	Familial adenomatous polyposis 3	2024-03-29	criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000657657	SCV005197023	pathogenic	not provided	2022-05-27	criteria provided, single submitter	clinical testing
OMIM	RCV000172911	SCV000223893	pathogenic	Familial adenomatous polyposis 3	2015-06-01	no assertion criteria provided	literature only
Eurofins Ntd Llc (ga)	RCV000657657	SCV000705556	uncertain significance	not provided	2017-01-13	flagged submission	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000172911	SCV001551973	pathogenic	Familial adenomatous polyposis 3		no assertion criteria provided	clinical testing	This pathogenic variant is denoted NTHL1 c.268C>T at the cDNA level and p.Gln90Ter (Q90X) (aka: NM_001318193.2:c.244C>T; NP_001305122.2:p.Gln82Ter) at the protein level. The substitution creates a nonsense variant, which changes a Glycine to a premature stop codon (CAG>TAG), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been observed in several individuals with colorectal cancer and/or adenomas (Dallosso 2008, Rivera 2015, Timofeeva 2015, Weren 2015). Weren et al. (2015) identified NTHL1 Gln90Ter in the homozygous state in 7 individuals from three families with a history of multiple colorectal adenomas and/or colorectal cancer. Additionally, Rivera et al. (2015) identified NTHL1 Gln90Ter in the compound heterozygous state with a canonical splice variant, confirmed to be in trans through familial testing, in an individual with colon cancer, multiple colorectal adenomas, and other neoplasms. Lastly, other studies identified NTHL1 Gln90Ter in the homozygous or compound heterozygous state in several unrelated individuals with colorectal adenomas and colorectal cancer (Chubb 2016, Belhadj 2017, Broderick 2017). Based on currently available information, we consider NTHL1 Gln90Ter to be pathogenic. Of note, NTHL1-Associated Polyposis (NAP) is a recessive condition associated with two pathogenic variants on opposite chromosomes in NTHL1. Although this variant is considered pathogenic, a second pathogenic variant, as would be required for expression of the recessive condition NAP, was not detected in this individual. We cannot exclude the possibility that this patient harbors a second disease-causing NTHL1 pathogenic variant that is undetectable by this test. NTHL1 has only recently been described in association with cancer predisposition and the risks are not well understood. Based on available data, the presence of two pathogenic variants in NTHL1 is indicative of NTHL1-Associated Polyposis (NAP), an autosomal recessive condition that may confer an increased risk for colorectal cancer and polyps. Although the development of colorectal cancer and attenuated polyposis appears to be the predominant feature of NAP, multiple case reports have described individuals with NAP to have developed multiple extracolonic neoplasms, including breast, endometrial, bladder, and skin cancers as well as several benign findings (Rivera 2015, Weren 2015, Belhadj 2017). The National Comprehensive Cancer Network has management guidelines for individuals with two pathogenic variants in NTHL1 (NCCN) (ClinVar- GeneDx; modified)
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000657657	SCV001744389	pathogenic	not provided		no assertion criteria provided	clinical testing
GenomeConnect - Invitae Patient Insights Network	RCV000172911	SCV001749753	not provided	Familial adenomatous polyposis 3		no assertion provided	phenotyping only	Variant reported in multiple Invitae PIN participants. Variant interpreted as Pathogenic and reported most recently on 6/19/2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000657657	SCV001807844	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000657657	SCV001919639	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000657657	SCV001968527	pathogenic	not provided		no assertion criteria provided	clinical testing
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	RCV000172911	SCV004041715	pathogenic	Familial adenomatous polyposis 3	2023-10-09	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003416065	SCV004116067	pathogenic	NTHL1-related disorder	2024-07-22	no assertion criteria provided	clinical testing	The NTHL1 c.268C>T variant is predicted to result in premature protein termination (p.Gln90*). This variant has been reported in the homozygous or compound heterozygous state in individuals with multiple colorectal adenomas and an increased susceptibility to colorectal, endometrial, skin, breast and bladder cancer (Rivera et al. 2015. PubMed ID: 26559593; Weren et al. 2015. PubMed ID: 25938944; Belhadj et al. 2017. PubMed ID: 27720914). This variant was found in the homozygous state in seven individuals from three families that had a history of colorectal adenomas and/or colorectal cancer (Weren et al. 2015. PubMed ID: 25938944). Of note, the three affected women in this study all developed endometrial cancer. Functional studies in B-lymphocytes from homozygous carriers indicate that this variant results in nonsense mediated decay and a ten-fold reduction in NTHL1 RNA expression in comparison to controls (Weren et al. 2015. PubMed ID: 25938944). This variant is reported in 0.35% of alleles in individuals of European (Finnish) descent in gnomAD and is interpreted as pathogenic by the vast majority of submitters in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/192319/). Nonsense variants in NTHL1 are expected to be pathogenic. This variant is interpreted as pathogenic for autosomal recessive NTHL1-related cancer predisposition.